Regulatory elements and transcription factors controlling basal and cytokine-induced expression of the gene encoding intercellular adhesion molecule 1

Abstract

The gene encoding intercellular adhesion molecule 1 (ICAM-1) is transcriptionally induced in response to inflammatory and immunomodulatory cytokines. To investigate the mechanisms controlling ICAM-1 gene expression, we have identified regulatory DNA sequences responsible for maintaining basal and mediating induced transcription in response to tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ). Regulatory elements centered 115, 60, and 40 bp upstream from the ICAM-1 transcription start site were implicated in cytokine-independent gene expression. Regulatory elements dedicated to TNF-α and IFN-γ were identified 190 and 90 bp, respectively, upstream from the ICAM-1 transcription start site. A combination of mutagenesis and DNA- binding assays revealed that the TNF-α response element is composite, consisting of binding sites for both C/EBP and NF-κB. The IFN-γ response element behaved as a simple regulatory element that selectively binds to an IFN-γ-inducible activity composed, at least in part, of p91. These observations provide a framework for understanding how extracellular signals dynamically regulate the adhesive properties of mammalian cells.